Worldwide, tuberculosis remains a leading cause of death. There are approximately 8 million active cases of tuberculosis per year, with 3 million deaths annually. About 1.7 billion people (one-third of world's population) are estimated to harbor the latent Mycobacterium tuberculosis infection [Kochi, A. Tubercle. 1991, 72, 1-6]. Individuals with latent tuberculosis carry 2 to 23% lifetime risk of reactivation of the disease later in life [Parrish, N M., Dick, J D., and Bishai, W R., Trends. Microbial. 1980, 6, 107-112]. In addition, immunosuppressive conditions including human immunodeficiency virus (HIV) infection has dramatically increased the risk of reactivation of tuberculosis.
The emergence of drug resistant pathogens renders the current mode of treatment very difficult and in many cases completely ineffective. Treatment of multi-drug resistant varieties of tuberculosis is difficult, and the disease often carries a high rate of mortality, particularly in developing countries. It is estimated that in the next twenty years over one billion people will be newly infected with tuberculosis with nearly 35 million people succumbing to the disease [WHO Fact Sheet No. 104, Global Alliance For TB Drug Development: Executive Summary of the Scientific Blueprint for TB Development; http://www.who.int/inf-fs/en/fact104.html]. With the emergence of HIV related tuberculosis, the disease is assuming alarming proportions as one of the killer diseases in the world today. The World Health Organization (WHO) has declared as a priority the need to immediately control tuberculosis infection for prevention of the spread of drug resistant strains.
One problem with current tuberculosis therapies is the shift of M. tuberculosis into a dormant or latent state. Thus, while the treatment of active tuberculosis with the currently prescribed combination drug regimen reduces the bacterial burden by a substantial amount, a proportion of bacilli shift into dormancy and survive in the host for months or years without producing any overt disease. However, later the bacilli can reactivate resulting in active tuberculosis once again. The recurrence of tuberculosis these days is considered to be the result of the reactivation of latent organisms which survive in the host [Stead, W W., Am. Rev. Respir. Dis., 1982, 95, 729-745; Stead, W W., Kerby, G R., Schleuter, and Jordahl, C W., Ann. Intern. Med., 1968, 68, 731-745].
The first drug used to combat M. tuberculosis was streptomycin in 1944, which was found to inhibit the growth of M. tuberculosis. A few classes of compounds have been introduced into clinical practice in the last 30 years, such as:
a) Long acting rifamycins e.g., rifapentine, rifabutin, and rifalazil [Javis, B., Lamb, H M., Drugs, 1998, 56, 607-616; McGregor, M M., Olliaro, P., Wolmarans, L., Am. J. Respir. Crit. Care Med., 1996, 154, 1462-1467; Shoen, C M., DeStefano, M S., Cynamon, M H., Clin. Infect. Dis., 2000, 30(Suppl. 3), S288-S29];
b) Fluoroquinolone compounds e.g. levofloxacin, moxifloxacin, and gatifloxacin [Ji, B., Lounis, N., Truffot-Pernot, C., Grosset., Antimicrob. Agents Chemother., 1995, 39, 1341-1344; Miyazaki, E., Miyazaki, M., Chen, J M., Chaisson, R E., Bishai, W R., Antimicrob. Agents Chemother., 1999, 43, 85-89; Fung-Tomc, J., Minassian, B., Kolek, B., Washo, T., Huczko, E., Boner, D., Antimicrob. Agents Chemother., 2000, 45, 437-446];
c) Oxazolidinone compounds [Cynamon, M H., Klemens, S P., Sharpe, C A., Chase, S C., Antimicrob. Agents Chemother., 1999, 43, 1189-1191]; and
d) Niroimidazopyrans [Strover, C K., Warrener, P., VanDevabter, D., Nature, 2000, 405, 962-966].
However, none of these compounds has shown the desired potential to effectively treat multi-drug resistant and/or latent tuberculosis.
Rifapentine and rifalazil have shown effectiveness in treating tuberculosis through administration of lesser (intermittent therapy) doses of the drugs and a combination of the two drugs is also reported to be more effective in preventing latent tuberculosis than rifampicin. However, since these drugs have the same pharmacophore as rifampicin their activity spectrum against the resistant strains has not improved significantly. These molecules are rather ineffective against multi-drug resistant strains of M. tuberculosis. Further, many of these compounds have proved to be toxic.
A number of drugs, such as p-aminosaliscyclic acid, isoniazid, pyrazinamide, ethambutol, ethionamide, rifampicin etc. have been used either alone or in combination for treatment of tuberculosis. These drugs were found to be more effective than streptomycin in treating patients infected with the streptomycin resistant strains, thereby ushering in an era of effective treatment of tuberculosis.
Currently, the treatment of tuberculosis consists of administering a combination of four first line drugs, viz. isoniazid, rifampicin, ethambutol and pyrazinamide, administered individually as a single drug formulation or as a fixed dose combination. For effective treatment the abovementioned four first line drugs are given to a patient in the initial or induction phase, during which the drugs are used in combination to kill the rapidly multiplying population of M. tuberculosis as well as to prevent the emergence of drug resistance. This is followed by a continuation phase during which sterilizing drugs, viz. isoniazid, rifampicin, and pyrazinamide are given to kill the intermittently dividing population of M. tuberculosis [Jindani, A., Aber, V R., Edwards, E A., Mitchison, D A., Am. Rev. Respir. Dis., 1980, 121, 39-49; Grosset, J., Tubercule., 1978, 59, 287-297; East African/British Medical Research Council Study in Am. Rev. Respir. Dis., 1977, 115, 3-8; Singapore Tuberculosis Service/British Medical Research Council in Am. Rev. Respir. Dis., 1979, 119, 579-585; British Thoracic Society and Tuberculosis Association in Am. Rev. Respir. Dis., 1982, 126, 460-462; Snider, D E., Rogowski, J., Zierski, M., Bek, E., Long, M W., Am. Rev. Respir. Dis., 1982, 125, 265-267].
While the abovemenioned combination of first line drugs together provide treatment against sensitive M. tuberculosis infection in 4 to 6 months time, such a combination therapy is not always successful, especially in patients harbouring multi-drug resistant strains. Also the long duration of treatment consisting of six months, more often than not, leads to unpleasant side effects. Further, compliance with the relatively long course of treatment is generally poor. Such non-compliance leads, more often than not, to treatment failure resulting in development of drug resistance.
The second line drugs, such as cycloserine, clofazimine, capreomycin etc. used for treatment, on the other hand, are more expensive, may cause severe side effects and are inferior to the first line drugs.
Substituted pyrrole derivatives constitute another class of compounds, which hold promise as antimycobacterial agents. Many pyrrole derivatives have been synthesized and tested for antitubercular activity [Deidda, D., et. al., Antimicrob. Agents Chemother., 1998, 3035-3037; Biava, M., et. al., J. Med. Chem Res., 1999, 19-34; Biava, M., et. al., Bioorg. & Med. Chem. Lett., 1999, 2, 2983-2988; Cerreto, F., et. al., Eur. J. Med. Chem., 1992, 27, 701-708; Gillet, C., et. al., Eur. J. Med. Chem.-Chimica Therapeutica., 1976, 11(2), 173-181; Raagno. R., et. al., Bioorg. & Med. Chem., 2000, 8, 1423-1432]. At best, the compounds disclosed therein are drug candidates not drugs since the reports contain no mention of in vivo activity and toxicity of the compounds disclosed therein against experimental tuberculosis in animal models. Hence, the compounds are more of academic rather than any commercial interest.
Hence, there is an urgent need to develop newer regimens that can be used to prevent, treat and/or reduce tuberculosis and/or eliminate the threat of multi-drug resistant tuberculosis and/or latent tuberculosis.
An alternative regimen should be superior to the existing regimen so as to:
a) shorten the total duration of treatment and/or significantly reduce the total number of doses;
b) provide an effective treatment of the multi-drug resistant varieties;
c) provide more effective treatment of latent tuberculosis; and
d) minimize or prevent side effects.
In our PCT Application No. PCT/IN02/00189 (WO 04/026828 A1) we have described several substituted pyrrole derivatives and pharmaceutically acceptable salts thereof, which have demonstrated good to excellent inhibitory activity against the susceptible and drug resistant strains of M. tuberculosis. The MIC value of some of the most active compounds against sensitive and multi-drug resistant strains of M. tuberculosis were in the range of 0.12 to 0.5 μg/ml. Further, some of the compounds have also demonstrated therapeutically significant in vivo activity against M. tuberculosis infected animals and also found to be safe having an LD50 value of about 700 mg/kg in mice as against 133 mg/kg for isoniazid. Moreover, the pharmacokinetic profile of the compounds are excellent. The subject matter of PCT Application No. PCT/IN02/00189 (WO 04/026828 A) is incorporated herein by reference.
The present inventors have found that a number of the pyrrole derivatives disclosed in PCT Application No. PCT/IN02/00189 (WO 04/026828 A1) provide a synergistic effect when used in combination with some of the front line drugs, thereby providing a new treatment of tuberculosis, including multi-drug resistant varieties and latent tuberculosis. The treatments described herein are superior to the drug regimens known in the prior art.